Drug combinations such as acetaminophen with codeine (Tylenol III) or acetaminophen with oxycodone (Lortab) produce analgesia that is additive or synergistic. The rational for using such combinations is to reduce the dose of each analgesic, and thus reduce adverse effects and toxicity, while retaining or increasing analgesic efficacy. These acetaminophen combinations have greater efficacy for moderate to severe pain.
For many types of pain (e.g., common headache, osteoarthritis) acetaminophen has equal potency and efficacy to acetylsalicylic acid (aspirin). However, the safety of acetaminophen has been questioned. There are approximately 100,000 cases of acetaminophen overdose annually, with approximately 30 deaths resulting. (Clissold, 1980; McGoldrick et al. 1997). Acetaminophen has a toxic metabolite, N-acetyl-benzoquinoneimine (NAPQI), which depletes hepatic and renal glutathione, a cytoprotective endogenous metabolite (Mason & Fischer, 1986; Mitchell et al., 1983). Hepatic and renal toxicity with acetaminophen can occur at doses only 4- to 8-fold higher than the maximum recommended analgesic dose (Neuberger et al., 1980). Pharmaceutical combinations that contain acetaminophen and a centrally acting analgesic may be even more dangerous than acetaminophen alone. With repeated use these combinations require higher doses to produce the same analgesic effect because of an increase in tolerance. As the dose of the combination is increased to compensate for analgesic tolerance, the safety of the drug decreases as the higher doses of the acetaminophen component increase hepatic and renal toxicity.
In U.S. Pat. No. 5,554,636 (Bazan et al.) and U.S. Pat. No. 5,621,110 (Bazan et al.), two of the inventors herein disclosed the series of N-acylated 4-hydroxyphenylamine derivatives linked via an alkylene bridge to the nitrogen atom of a 1,2-benzisothiazol-3(2H)-one 1,1-dioxide group along with the process for their preparation and methods of their use for alleviating pain. The disclosures of these patents are incorporated herein by reference. The SCP series is structurally depicted by the following general formula: wherein n is a number from 1 to 5. These new non-narcotic analgesics surprisingly possess high analgesic activity, do not suppress blood coagulation, and display little hepatotoxic effect. When the term “SCP series” is used herein, it is understood that any of the pharmaceutically suitable salts thereof are included by the term.
The analgesic profiles of the SCP series are at least as good as that of acetaminophen. As expected, both types of drugs show little or no activity in the tail-flick and hotplate tests when compared with codeine. SCP-1 is more potent in the abdominal stretch, formalin, and Freund's adjuvant-induced inflammation assays of analgesia than acetaminophen. SCP-1 is lower in toxicity, and, of even greater importance, lower in hepatotoxicity (Paul et al., 1998). All of these properties make SCP-1 and related derivatives potentially very useful pharmacologic agents.